Mullerian Inhibiting Substance (MIS, AMH) is a distinct member of the transforming growth factor beta (TGFbeta) superfamily. Members of this superfamily are polypeptide growth factors that exhibit diverse effects on normal cell growth, adhesion, mesenchymal-epithelium interactions, cell differentiation and programmed cell death. Mammalian reproductive tract development begins with the selective differentiation of either the Wolffian or Mullerian ducts which give rise to the male or female reproductive tract, respectively. In males, testicular production of MIS triggers destruction of the Mullerian duct, which we hypothesize to involve programmed cell death. The molecular dissection of the MIS signaling pathway provides a unique system to study hormonal induction of programmed cell death between adjacent cellular layers. This type of cell death is postulated to specify much of the morphological remodeling and adjustment of cell numbers during development. We seek to define the molecular death signals emanating from the paramesonephric mesenchyme that initiate apoptosis of the Mullerian epithelium. Presently, only the MIS ligand the MIS Type II receptor have been identified in the MIS signal transduction pathway. Our proposed studies are designed to delineate other components of MIS signaling cascade via the following aims: 1) Identify the Type I MIS receptor. 2) analyze the biochemical signaling events following activation of the Type I & II heteromeric complex. 3) Identify the downstream MIS-induced death signals that result in the involution of the Mullerian duct. These studies will provide a basic biochemical framework for understanding how TGF-beta-like hormones elicit changes in cellular identity, morphology, and cell number using a unique model system. Moreover, given the potential role of MIS and other gonadal TGFbeta-like hormones to act an antiproliferative signals or tumor suppressor genes, our research may also shed light on possible mechanisms that contribute to abnormal cell growth and tumor progression in the reproductive system.